The overall goal of the proposed research is to develop orally active inhibitors of myeloperoxidase MPO as a treatment forAlzheimer's disease. MPO is an abundant enzyme in leukocytes but its expression can be induced in astrocytes in Alzheimer's disease. This abnormal expression of MPO can lead to the oxidation of lipids and proteins leading to tissue damage and cell death resulting in loss of memory. A potent and safe inhibitor of MPO could be helpful in the treatment of Alzheimer's disease. We have developed novel mouse model to evaluate the role of MPO in Alzheimer's disease. In Specific Aim 1 We propose to improve the potency of hits identified in a screen looking for inhibitors of MPO. In Specific Aim 2 we propose to test several of the MPO inhibitors in a mouse model of Alzheimer's disease. The mice will be evaluated using both biochemical and behavioral/cognitive tests.